The present invention relates generally to the field of the diagnosis of ailments of said gastrointestinal tract, and particularly, to an ingestible device that travels in the gastrointestinal tract and performs diagnosis therein.
The impact of cancer of the gastrointestinal tract is grave. In spite of enormous expenditures of financial and human resources, early detection of malignant tumors remains an unfulfilled medical goal. While it is known that a number of cancers are treatable if detected at an early stage, lack of reliable screening procedures results in their being undetected and untreated.
There are other gastrointestinal-tract disorders, which similarly require reliable screening and diagnostic procedures for early detection and treatment. These include, for example, irritable bowel syndrome, fluxional diarrhea, ulcerative colitis, collagenous colitis, microscopic colitis, lymphocytic colitis, inflammatory bowel disease, Crohn's disease, infectious diarrhea, ulcerative bowel disease, lactase deficiency, infectious diarrhea, amebiasis, and giardiasis.
To some extent, simple diagnostic procedures for gastrointestinal pathologies may be employed, as part of routine checkups. For example, sampling for blood in the stool is a screening technique for digestive tract cancer. However, this procedure is not very sensitive, because blood is released when comparatively large polyps develop. Sometimes, there is no release of blood to the stool until very late in the development of the disease.
Additionally, PCT International Application WO92/00402 PCT describes a non-invasive method for detecting gastric epithelial damage using a disaccharide such as sucrose, maltose or lactose which is orally administered to a patient. Blood and urine samples are then assayed, for the disaccharide, to determine the existence and extent of gastric epithelial damage. However, this method does not reliably detect damage of the intestinal tract.
For more reliable diagnoses, various forms of endoscopes and other imaging apparatus may be used.
Diagnosis of different conditions of the colon generally involves using a colonoscope. A typical colonoscope includes, at its distal end, with respect to an operator, a light source, a video chip, and a suction channel. These elements are all in communication with a proximal end of the colonoscope via wires and channels housed within a flexible tube. The distal end is inserted into a patient's rectum and can be maneuvered along the length of the colon. A colonoscope can be inserted far enough into a patient's colon for the distal end to enter the patient's cecum. The tip of the colonoscope can also be maneuvered through the ileo-cecal valve into the terminal ileum.
A colonoscope provides a visual image only of the region of the colon that is immediately near the light source and video chip, yielding visual information for only a small region of the colon at any given time. Lesions in a patient's colon typically are identified by progressive and painstaking visual examination of the entire colon. However, a single colonoscopy is often not sufficient to identify the source of colorectal bleeding which is typically sporadic and in many cases would be best located by observing the entire colon over a period of time.
Various attachments to a colonoscope allow small surgical procedures, such as tissue biopsies, to be carried out during a colonoscopic examination.
Endoscopy of the small intestine is also known. U.S. Pat. No. 5,984,860, to Shan, entitled, “Pass-through duodenal enteroscopic device,” whose disclosure is incorporated herein by reference, describes a tethered ingestible, enteroscopic video camera, which utilizes the natural contraction wave of the small intestine to propel it through the small intestine at about the same speed as any other object therein. The video camera includes an illumination source at its forward end. Covering the camera lens and illumination source is a transparent inflatable balloon, adapted to gently expand the small intestine immediately forward the camera for better viewing. A small diameter communication and power cable unwinds through an aperture in the rear of the camera as it moves through the small intestine. Upon completion of movement through the small intestine the cable is automatically separated, permitting the cable to be withdrawn through the stomach and intestine. The camera continues through the large intestine and passes from the patient through the rectum.
The aforementioned endoscopes, while providing means to access and visualize portions of the gastrointestinal track, do not provide means of detecting gastrointestinal pathologies, which are not clearly visible. In particular, they do not provide means for localization and differentiation of occult tumors. Typically, a large tumor is readily located by visualization. Yet, for subsequent operative success, as well as for the success of other forms of treatment, it is necessary to somehow locate tumors in their occult stage, when they cannot be found by sight and feel.
The use of radiolabeled immunoglobulin for tumor localization was shown to be possible in 1959 when Day et al. radiolabeled isolated antifibrin. (Day, E. O.; Planisek, J. A.; Pressman D: “Localization of Radioiodinated Rat Fibrinogen in Transplanted Rat Tumors”, J. Natl. Cancer Inst. 23: 799-812, 1959). Fibrin, while not a tumor-specific antigen, was known to have a frequency of presence in tumors due to the inflammatory process-accompanying invasion. Day et al. demonstrated that a protein in high concentration in tumor sites could be used to localize tumors. The antibodies against human fibrin and ferritin were used in attempts to employ specific immunoglobulins for diagnosis.
Since the work of Day et al, in 1959, an expanding number of monoclonal antibodies have received FDA approval. Examples, applicable to gastrointestinal tract tumors, include the following:    1. CEA-Scan is a Tc99m-labeled monoclonal antibody fragment, which targets CEA—produced and shed by colorectal carcinoma cells. The use of anti-CEA monoclonal antibody has been recommended as the only marker to estimate prognosis and response to therapy. Anti-CEA monoclonal antibody may also be labeled by other radioisotopes, for example, iodine isotopes. (Jessup J M. 1998, Tumor markers—prognostic and therapeutic implications for colorectal carcinoma, Surgical Oncology; 7: 139-151.)    2. In111-Satumomab Pendetide (Oncoscint®) is designed to target TAG-72. TAG-72 is a mucin-like glycoprotein expressed in human colorectal, gastric, ovarian, breast and lung cancers. It is rarely expressed in normal human adult tissues. (Molinolo A; Simpson J F; et al. 1990, Enhanced tumor binding using immunohistochemical analyses by second generation anti-tumor-associated glycoprotein 72 monoclonal antibodies versus monoclonal antibody B72.3 in human tissue, Cancer Res. 50(4): 1291-8.)    3. Lipid-Associated Sialic Acid (LASA) is a tumor antigen, which for colorectal carcinoma LASA, has a similar sensitivity as CEA but a greater specificity for differentiating between benign and malignant lesions. (Ebril K M, Jones J D, Klee G G. 1985, Use and limitations of serum total and lipid-bound sialic acid concentrations as markers for colorectal cancer, Cancer; 55:404-409.)    4. Matrix Metaloproteinase-7 (MMP-7) is a proteins enzyme, believed to be involved in tumor invasion and metastasis. Its expression is elevated in tumor tissue compared to normal tissue and may be a potential marker for tumor aggressiveness and traditional staging. (Mori M, Barnard G F et al. 1995, Overexpression of matrix metalloproteinase-7 mRNA in human colon carcinoma Cancer; 75: 1516-1519.)
Additionally, pharmaceuticals may be used as markers for nonmalignant pathologies, such as gastrointestinal inflammations and infections. Examples include the following:    1. Ga67 citrate binds to transferrin and is used for detection of chronic inflammation. (Mettler F A, and Guiberteau M J, Eds. 1998, Inflammation and infection imaging. Essentials of nuclear medicine. Fourth edition. Pgs: 387-403.)    2. Nonspecific-polyclonal immunoglobulin G (IgG) may be labeled with both In111 or Tc99m, and has a potential to localize nonbacterial infections. (Mettler F A, and Guiberteau M J, ibid.)    3. Radio-labeled leukocytes, such as such as In111 oxine leukocytes and Tc99m HMPAO leukocytes are attracted to sites of inflammation, where they are activated by local chemotactic factors and pass through the endothelium into the soft tissue. Labeled leukocytes in the gastrointestinal tract are nonspecific and may indicate a number of pathologies, including Crohn's disease, ulcerative colitis, psudomembranous colitis, diverticulosis, various gastrointestinal infections, fistulas, ischemic or infracted bowel. (Mettler F A, and Guiberteau M J, ibid; Corstens F H; van der Meer J W. 1999. Nuclear medicine's role in infection and inflammation. Lancet; 354 (9180): 765-70.)
The particular choice of a radionuclide for labeling antibodies is dependent upon its nuclear properties, the physical half-life, the detection instruments' capabilities, the pharmacokinetics of the radiolabeled antibody, and the degree of difficulty of the labeling procedure. Examples of radionuclides used for labeling antibodies include Technetium Tc99m, Iodine I125, I123, I131, and I133, Indium In111, Gallium Ga67, thallium Tl201, fluorine F18 and P32.
Nuclear-radiation imaging of radionuclide-labeled antibodies is a subject of continued development and study. A particular difficulty in using radionuclides is that blood-pool background radioactivity has caused ordinary scintigrams to prove difficult to interpret. Computer subtraction of radioactive blood-pool background radioactivity has been attempted to enhance imaging. Yet the ability to detect occult tumors has remained low.
An attempt to overcome the blood-pool background radioactivity is described in U.S. Pat. No. 4,782,840 to Martin, Jr., et al., entitled, “Method for locating, differentiating, and removing neoplasms,” whose disclosure is incorporated herein by reference. Martin, Jr., et al describe a method for improved localization, differentiation and removal of neoplastic tissue in animals. The improved method commences with the administering to the animal of an effective amount of a labeled antibody specific for neoplastic tissue and labeled with a radioactive isotope exhibiting specific photon emissions of energy levels. A waiting period follows, to permit the labeled antibody to preferentially concentrate in any neoplastic tissue present in the animal and to allow blood-pool background radioactivity to decrease, thus increasing the ratio of photon emissions from neoplastic tissue to background photon emissions in the animal. Thereafter, a general background photon-emission count is determined, for the tissue. Once the background count has been determined, the tissue suspected of being neoplastic is accessed by surgical means, and a handheld probe is manually maneuvered along that tissue. The probe is configured for fascicle hand positioning and maneuvering. The probe is characterized by a collimatable radiation detector having a selective photon entrance and having an output deriving discrete signals responsive to photon emissions when the entrance is positioned immediately adjacent thereto. The probe further comprises amplifier means having an input coupled with the radiation detector output and responsive to the discrete signals to provide corresponding amplified output pulses. Finally, the probe comprises readout means responsive to the output pulses and actuable to an initial condition for commencing the provision of a perceptible indication of an indicia corresponding to the number of the output pulses received. From the perceptible indication, the extent of tissue exhibiting a number of output pulses having a value above background output pulses is determined and such tissue is removed surgically.
Due to the proximity of the detection probe to the labeled antibody, the faint radiation emanating from occult sites becomes detectable. This is in part because of the inherent application of the approximate inverse square law of radiation propagation, and in part because the collimatable radiation detector may be maneuvered at various angles with respect to the suspected neoplastic tissue, so that at some positions, the collimator is aligned with the source of radiation. The procedure now is known as radioimmunoguided surgery, or RIGS™. (RIGS is a registered trademark of Neoprobe Corporation of Dublin, Ohio).
The RIGS™ system for surgery is successful because the blood-pool background of the circulating radiolabeled antibody is cleared from the body prior to imaging with the probe. As a consequence, the photon emissions or radiation emitted at minute tumors, compared to surrounding tissue, become detectable. Fortuitously, the radiolabeled antibody is capable of remaining bound to or associated with neoplastic tissue for extended periods of time with the radio tag still bound thereto. Even though the accretion of radioactivity at the tumor site decreases over time, the blood-pool background at surrounding tissue (relative to the tumor sites) decreases at a much greater rate.
RIG instrumentation generally includes two basic components, a hand-held probe, as described hereinabove, and a control console, in electrical communication with hand-held probe, via a flexible cable. The control console is located within the operating room facility but out of the sterile field, while the hand-held probe and forward portions of its associated cable are located within that field. The hand-held radiation-detecting probe is relatively small and performs in conjunction with a cadmium-zinc-telluride detector or crystal.
Further work continued to improve the sensitivity of RIGS™ to the minute number of photons that may be emitted from an occult tumor. U.S. Pat. No. 4,801,803 to Denen, et al., entitled, “Detector and localizer for low energy radiation emissions,” whose disclosure is incorporated herein by reference, describes a probe particularly suited for use in immuno-guided surgery capable of detecting very faint gamma emissions and thereby localizing cancerous tumor. Detection is achieved under room temperature conditions using a crystal such as cadmium telluride. To achieve the extreme sensitivity capabilities of the apparatus, an instrumentation approach has been developed in which the somewhat fragile crystal is securely retained in isolation from externally induced incidents otherwise creating excessive noise. Microphonic effects are minimized through employment of a sequence of materials exhibiting divergent acoustic impedance. Capacitive effects caused by minute intercomponent movements are controlled to acceptable levels.
Additionally, a preamplifier is incorporated within the probe itself, which employs an integrator stage front end combining a field effect transistor and bipolar device with a very small feedback capacitance of less than one picofarad. A bootstrap technique is utilized to enhance the amplification of the bipolar amplification stage. Pulse related signals outputted from the device are normalized and compared to produce pulse data, which are analyzed. In one mode of operation a siren effect is employed to guide the surgeon towards emission sources.
The aforementioned probe is directed at low energy radionuclides, such as I125. Additionally, the distribution of radiolabeled antibody with the nuclide is quite sparse so that background emissions can be minimized and the ratio of tumor-specific counts received to background counts can be maximized. The probe instrument and related control circuitry has been assigned the trade designation “NEOPROBE” instrument.
Further improvements to the “NEOPROBE” instrument are described in U.S. Pat. No. 5,151,598 to Denen, entitled, “Detector and localizer for low energy radiation emissions,” whose disclosure is incorporated herein by reference. Further improvements include controlling capacitive and piezoelectric effects occasioned by the most minute of intercomponent movements. Additionally, compressive retention of the crystal and electrical contacts is employed in conjunction with electrically conductive but pliable surface supports.
Additionally, improvements to the “NEOPROBE” instrument are described in U.S. Pat. No. 4,893,013 to Denen et al., entitled, “Detector and Localizer for Low Energy Radiation Emissions,” and U.S. Pat. No. 5,070,878 to Denen, entitled, “Detector and localizer for low energy radiation emissions,” whose disclosures are incorporated herein by reference. The probe includes a cadmium telluride crystal, secured in a light-tight environment. A noise immune structuring of the probe and crystal combination includes the utilization of electrically conductive, compliant cushion layer located at one face of the crystal in conjunction with freely abutting biasing and ground contacts. A nylon, resilient retainer is positioned in tension over the assemblage of crystal, ground and biasing contacts and compliant layers to achieve a compressively retained assemblage. A dead air space is developed between the forward facing window of the probe and the crystal retaining assemblage.
To derive data representing the presence or absence of occult tumor, a microprocessor-driven complex system of analysis continuously works to statistically evaluate validated counts or gamma strikes to apprise the surgeon of the presence or absence of occult neoplastic tissue. U.S. Pat. No. 4,889,991 by Ramsey and Thurston, entitled, “Gamma Radiation Detector with Enhanced Signal Treatment,” whose disclosure is incorporated herein by reference, describes an algorithm under which such an evaluation takes place. Accordingly, a hand-held gamma radiation probe, such as NEOPROBE instrument, is employed, in conjunction with a control function which provides an enhanced audio output, directed for cueing the user to the source position, as he maneuvers the probe along the tissue. The probe is positioned at a location on the animal body representing background radiation and a squelch low count rate is developed therefrom. The squelch low count rate is multiplied by a range factor to develop a squelch high-count rate and frequencies are developed from a look-up frequency table from lowest to highest in correspondence with the developed high and low squelch count rates. Slew rate limiting of the count rates is provided by development of a squelch delta value representing the difference between the squelch high and low count rates divided by a time element. Selection of frequencies for audio output from the frequency table is limited by the value of the squelch delta value. Weighting of received radiation counts is carried out continuously to develop count rate values used by the system.
U.S. Pat. No. 6,259,095, to Boutun, et al., entitled, “System and apparatus for detecting and locating sources of radiation,” whose disclosure is incorporated herein by reference, describes further improvements to the aforementioned probes of Neoprobe Corporation. The apparatus incorporates a large window display utilizing icon imagery to identify counting functions such as target count and background. A variety of radionuclide modes of operation can be selected by the operator and the system automatically defaults to detector bias selection and window reference voltage selection in correspondence with the elected radionuclide. A bar graph readout apprises the user of the amount of time or count level remaining in a target or background procedure and the flashing of icon identifiers occurs during such procedures. Pulse validation is improved by the utilization of a discriminator, which evaluates pulse width.
In spite of these advances, background radiation remains an obstacle that limits the probe sensitivity to occult tumors, and there are continued endeavors to minimize its effect.
Optical fluorescence spectroscopy is a known imaging technique.
When a sample of large molecules is irradiated, for example, by laser light, it will absorb radiation, and various levels will be excited. Some of the excited states will return back substantially to the previous state, by elastic scattering, and some energy will be lost in internal conversion, collisions and other loss mechanisms. However, some excited states will create fluorescent radiation, which, due to the distribution of states will give a characteristic wavelength distribution.
Some tumor-marking agents give well-structured fluorescence spectra, when irradiated by laser light. In particular, hematoporphyrin derivatives (HPD), give a well-structured fluorescence spectrum, when excited in the Soret band around 405 nm. The fluorescence spectrum shows typical peaks at about 630 and 690 nm, superimposed in practice on more unstructured tissue autofluorescence. Other useful tumor-marking agents are dihematoporphyrin ether/ester (DHE), hematoporphyrin (HP), polyhematoporphyrin ester (PHE), and tetrasulfonated phthalocyanine (TSPC), when irradiated at 337 nm (N2 laser)
U.S. Pat. No. 5,115,137, to Andersson-Engels, et al, entitled, “Diagnosis by means of fluorescent light emission from tissue,” whose disclosure is incorporated herein by reference, relates to improved detection of properties of tissue by means of induced fluorescence of large molecules. The tissue character may then be evaluated from the observed large-molecule spectra According to U.S. Pat. No. 5,115,137, the spectrum for tonsil cancer is clearly different from normal mucosa, due to endogenous porphyrins.
Similarly, U.S. Pat. No. 4,785,806, to Deckelbaum, entitled, “Laser ablation process and apparatus,” whose disclosure is incorporated herein by reference, describes a process and apparatus for ablating atherosclerotic or neoplastic tissues. Optical fibers direct low power light energy at a section of tissue to be ablated to cause the section to fluoresce. The fluorescence pattern is analyzed to determine whether the fluorescence frequency spectrum is representative of normal or abnormal tissue. A source of high power, ultraviolet, laser energy directed through an optical fiber at the section of tissue is fired only when the fluorometric analysis indicates that it is directed at abnormal tissue.
Additionally, U.S. Pat. No. 4,682,594, to Mok, entitled, “Probe-and fire lasers,” whose disclosure is incorporated herein by reference, describes a method and apparatus of irradiating a treatment area within a body, such as blood vessel plaque. The method includes initially administering to the patient a non-toxic atheroma-enhancing reagent which causes the plaque to have a characteristic optical property when illuminated with a given radiation, introducing a catheter system including fiberoptic cable means into the artery such that the distal end thereof is operatively opposite the plaque site, introducing into the proximal end of the fiberoptic cable means the given radiation, photoelectrically sensing at the proximal end the characteristic optical property to generate a control signal, and directly under the control of the control signal transmitting via the cable means from the proximal end to the distal end, periodically occurring laser pulses until the characteristic optical property is no longer sensed.
A related fluorescence technique is described in U.S. Pat. No. 4,336,809 to Clark, entitled. “Human and animal tissue photoradiation system and method,” whose disclosure is incorporated herein by reference. It relates to utilizing certain dyes, which not only selectively stain neoplastic tissue but also fluoresce in response to irradiation. Additionally, they are photodynamically cytotoxic in response to a proper wavelength of light in the presence of oxygen within living tissue. One of the dyes that is presently preferred for these characteristics contains hematoporphyrin or hematoporphyrin derivatives that when administered intravenously remain at higher concentrations for longer periods of time in traumatized or malignant tumorous tissue than in normal tissue. This dye also has a strong absorption peak centered at a wavelength of approximately 407 nanometers and responds to excitation at about this wavelength by fluorescing at a wavelength of about 614 nanometers. This makes tumor diagnosis possible by injecting the dye, allowing it to concentrate in tumorous tissue, irradiating the tissue with deep blue violet light, and observing red fluorescence. Thus, the difference in the optical property of the stained tissue and the unstained healthy tissue improves the visualization of the treatment area. This same dye has a photodynamic absorption peak at a wavelength of about 631 nanometers and is cytotoxic to malignant tissue containing the dye when irradiated with red light of about this wavelength. For diagnostic purposes krypton ion laser was used for its 406.7/413.1 nanometer lines matching the 407 nanometer absorption peak of hematoporphyrin.
U.S. Pat. No. 6,258,576, to Richards-Kortum, et al., entitled, “Diagnostic method and apparatus for cervical squamous intraepithelial lesions in vitro and in vivo using fluorescence spectroscopy,” whose disclosure is incorporated herein by reference, relates to the use of multiple illumination wavelengths in fluorescence spectroscopy for the diagnosis of cervical cancer and precancer. In this manner, it has been possible to (i) differentiate normal or inflamed tissue from squamous intraepithelial lesions (SILs) and (ii) differentiate high grade SILs from non-high grade SILs. The detection may be performed in vitro or in vivo. Multivariate statistical analysis has been employed to reduce the number of fluorescence excitation-emission wavelength pairs needed to re-develop algorithms that demonstrate a minimum decrease in classification accuracy.
For example, the method of the aforementioned patent may comprise illuminating a tissue sample with electromagnetic radiation wavelengths of about 337 nm, 380 nm and 460 nm, to produce fluorescence; detecting a plurality of discrete emission wavelengths from the fluorescence; and calculating from the emission wavelengths a probability that the tissue sample belongs in particular tissue classification.
Ultrasound is another known imaging technique. Conventional ultrasonic probes are used for internal examinations in the field of obstetrics, gynecology, urology and the like.
U.S. Patent Application 20010020131, to Kawagishi, Tetsuya, et al., entitled, “Ultrasonic diagnosis system,” whose disclosure is incorporated herein by reference, describes an ultrasonic diagnosis apparatus that has an ultrasonic probe, having a plurality of arrayed transducer elements, a transmitting beam former for generating driving signals for driving transducer elements, and a receiving beam former for generating receiving signals based on echo signals received by transducer elements. The transmitting beam former generates driving signals so that phases of ultrasonic waves generated from transducer elements are aligned at multiple focal points. An image processor extracts harmonic components from receiving signals of ultrasonic waves having multiple focal points, and generates ultrasonic image data based on the harmonic components.
U.S. Pat. No. 5,088,500 to Wedel., et al., entitled, “Ultrasound finger probe and method for use,” whose disclosure is incorporated herein by reference, describes a method and apparatus for performing ultrasound rectal examinations, by providing an ultrasound transducer which is slipped over the physician's finger tip and then inserted into the patient's rectum, together with an apparatus for guiding medical instruments into the area to be imaged.
Similarly, U.S. Pat. No. 5,284,147, to Hanoaka, et al., entitled, “Ultrasonic probe to be installed on fingertip,” whose disclosure is incorporated herein by reference, relates to an ultrasonic probe to be inserted into the body of a subject for image-processing a diagnostic target thereof by ultrasonic waves transmitted to and received from the inside of the body. More particularly, it relates to an internal examination ultrasonic probe which can be directly installed on a palpation finger. The ultrasonic probe includes a transducer array for transmitting and receiving the ultrasonic waves; a housing for supporting the transducer array, which housing is provided with a device for installing a fingertip of an operator therein; and electric wiring members connected to the transducer array and extending from the housing to the outside so that transmission and reception signals of the ultrasonic waves are supplied therethrough.
Contrast agents may be used in conjunction with ultrasound imaging, for example as taught by U.S. Pat. No. 6,280,704, to Schutt, et al., entitled, “Ultrasonic imaging system utilizing a long-persistence contrast agent,” whose disclosure is incorporated herein by reference.
Temperature imaging for locating and detecting neoplastic tissue is also known. In the 1950's, it was discovered that the surface temperature of skin in the area of a malignant tumor exhibited a higher temperature than that expected of healthy tissue. Thus, by measuring body skin temperatures, it became possible to screen for the existence of abnormal body activity such as cancerous tumor growth. With the development of liquid crystals and methods of forming temperature responsive chemical substrates, contact thermometry became a reality along with its use in medical applications. Devices employing contact thermometry could sense and display temperature changes through indicators which changed colors, either permanently or temporarily, when placed in direct physical contact with a surface such as skin, reflecting a temperature at or near the point of contact. An abnormal reading would alert a user to the need for closer, more detailed examination of the region in question. However, the art in this area has been directed primarily at sensing and displaying temperatures on exterior skin surfaces. Thus, for example, the patent to Vanzetti et al. (U.S. Pat. No. 3,830,224) disclosed the placement of temperature responsive, color changing liquid crystals at various points in a brassiere for the purpose of detecting the existence of breast cancer, while the patent to Sagi (U.S. Re. No. 32,000) disclosed the use of radially arranged rows of temperature responsive indicators deposited on a disc for insertion into the breast-receiving cups of a brassiere for the same purpose.
Additionally, Tomatis, A., et al, studied reflectance images of 43 pigmented lesions of the skin (18 melanomas, 17 common melanocytic naevi and eight dysplastic naevi). Reflectance images were acquired by a telespectrophotometric system and were analyzed in the spectral range from 420 to 1040 nm, to discriminate melanoma from benign melanocytic entities. Different evaluations were carried out considering the whole spectrum, the visible and the near infrared. A total of 33 (76.7%) lesions were correctly diagnosed by the telespectrophotometric system, compared with 35 (81.4%) correct clinical diagnoses. Reflectance in the infrared band appears diagnostically relevant.
It is believed that the same principle may apply to internal body organs. An abnormally high temperature at the surface of an internal organ when compared with surrounding tissue may also indicate the likelihood of a medical problem. Thus, there are advantages to diagnostic measurements of temperature in body cavities for early indications of abnormalities. These may provide simple, speedy, accurate and cost-effective solution to screening procedures.
U.S. Pat. No. 6,135,968, to Brounstein, entitled, entitled, “Differential temperature measuring device and method,” whose disclosure is incorporated herein by reference, describes a device and method for sensing temperatures at internal body locations non-surgically accessible only through body orifices. The device is particularly useful in medical applications such as screening for cancer and other abnormal biological activity signaled by an increase in temperature at a selected site. As applied to prostate examinations, the device is temporarily, adhesively affixed to a user's fingertip or to a mechanical probe. In the preferred embodiment, the device includes two temperature-sensing elements, which may include a plurality of chemical indicators. Each indicator changes color in response to detection of a predetermined particular temperature. When properly aligned and installed, the first element is located on the palmar surface of the fingertip while the second element is located on the dorsal surface of the fingertip. After an examination glove has been donned over the fingertip carrying the device, a prostate examination is performed during which the first element is brought into constant but brief contact with the prostate region and the second element is similarly, simultaneously brought into contact with a dermal surface opposing the prostate region. Upon withdrawal of the fingertip from the rectum and removal of the glove, the two temperature sensing elements may be visually examined in order to determine the temperatures detected by each one. A significant difference in observed temperatures indicates the possibility of abnormal biological activity and the need for further diagnostic or medical procedures.
Infrared thermography is a temperature imaging technique, which measures thermal energy emitted from the body surface without contact, quickly and dynamically, and produces a temperature image for analysis. Harzbecker K, et al. report, based on thermic observations in 63 patients and a control experiment in 15 persons, on experiences with thermography in the diagnosis of diseases, which are localized more profoundly in the thoracic cavity. (Harzbeeker K, et al., “Thermographic thorax diagnostics,” Z Gesamte Inn Med. Feb. 1, 1978; 33(3):78-80.)
Similarly, Dexter L I, Kondrat'ev V B. report data concerning the use of lymphography and thermography for the purpose of establishing a differential diagnosis in 42 patients with edema of the lower limbs of a different origin. A comparative estimation of different methods of the differential diagnosis indicated the advantages of infrared thermography. (Dexter L I, Kondrat'ev V B., “Thermography in differential diagnosis of lymphostasis in the lower limbs,” Vestn Khir Im I I Grek. 1976 June; 116(6):60-4.)
Electrical Impedance imaging is another known imaging technique for detecting tumors. Relying on inexpensive probes, it provides a simple screening procedure, particularly for breast cancer. (“Breast Cancer screening by impedance measurements” by G. Piperno et al. Frontiers Med. Biol. Eng., Vol. 2, pp 111-117). It involves systems in which the impedance between a point on the surface of the skin and some reference point on the body of a patient is determined. Sometimes, a multi-element probe, formed as a sheet with an array of electrical contacts is used, for obtaining a two-dimensional impedance map of the tissue, for example, the breast. The two-dimensional impedance map may be used, possibly in conjunction with other data, such as mammography, for the detection of cancer.
Rajshekhar, V., describes using an impedance probe having a single electrode to measure the impedance characteristics of lesions (“Continuous impedance monitoring during CT-guided stereotactic surgery: relative value in cystic and solid lesions,” Rajshekhar, V., British Journal of Neurosurgery, 1992, 6, 439-444). The objective of the study was to use the measurements made in the lesions to determine the extent of the lesions and to localize the lesions more accurately. The probe is guided to the tumor by CT and four measurements were made within the lesion as the probe passed through the lesion. A biopsy of the lesion was performed using the outer sheath of the probe as a guide to position, after the probe itself was withdrawn.
U.S. Pat. No. 4,458,694, to Sollish, et al., entitled, “Apparatus and method for detection of tumors in tissue,” whose disclosure is incorporated herein by reference, relates to apparatus for detecting tumors in human breast, based on the dielectric constants of localized regions of the breast tissue. The apparatus includes a probe, comprising a plurality of elements. The apparatus further includes means for applying an AC signal to the tissue, means for sensing electrical properties at each of the probe elements at different times, and signal processing circuitry, coupled to the sensing means, for comparing the electrical properties sensed at the different times. The apparatus thus provides an output of the dielectric constants of localized regions of breast tissue associated with the probe.
Similarly, U.S. Pat. No. 4,291,708 to Frei, et al., entitled, “Apparatus and method for detection of tumors in tissue,” whose disclosure is incorporated herein by reference, relates to apparatus for detecting tumors in human breast tissue. The apparatus includes means for determining the dielectric constants of a plurality of localized regions of human breast tissue. These include a bridge, which is provided with a circuit for automatically nulling the bridge while in operation. Means are further provided for measuring variations in the dielectric constants over a plurality of the regions and for indicating the possible presence of a tumor as result of the measurement. The apparatus may be utilized in carrying out a method of detecting tumors which includes the steps of applying a plurality of probe elements to breast tissue for sensing characteristics of localized regions thereof, applying an electrical signal to the probe elements for determining dielectric constants of localized regions of the tissue, sensing variations in the dielectric constants and determining the rate-of-change of dielectric constant at each of the localized regions.
U.S. Pat. Nos. 6,308,097, 6,055,452 and 5,810,742, to Pearlman, A. L., entitled, “Tissue characterization based on impedance images and on impedance measurements,” whose disclosures are incorporated herein by reference, describe apparatus for aiding in the identification of tissue type for an anomalous tissue in an impedance image comprising: means for providing an polychromic immitance map of a portion of the body; means for determining a plurality of polychromic measures from one or both of a portion of the body; and a display which displays an indication based on said plurality of polychromic measures.
Magnetic resonance imaging (MRI) is based on the absorption and emission of energy in the radio frequency range of the electromagnetic spectrum, by nuclei having unpaired spins.
The hardware components associated with an MRI imager are:    i. a primary magnet, which produces the Bo field for the imaging procedure;    ii. gradient coils for producing a gradient in Bo;    iii. an RF coil, for producing the BI magnetic field, necessary to rotate the spins by 90° or 180° and for detecting the NRI signal; and    iv. a computer, for controlling the components of the MRI imager.
Generally, the magnet is a large horizontal bore superconducting magnet, which provides a homogeneous magnetic field in an internal region within the magnet. A patient or object to be imaged is usually positioned in the homogeneous field region located in the central air gap for imaging.
A typical gradient coil system comprises an antihelmholtz type of coil. These are two parallel ring shaped coils, around the z axis. Current in each of the two coils flows in opposite directions creating a magnetic field gradient between the two coils.
The RF coil creates a B1 field, which rotates the net magnetization in a pulse sequence. They may be: 1) transmit and receive coils, 2) receive only coils, and 3) transmit only coils.
In this geometry, use of catheters equipped with miniature RF coils for internal imaging of body cavities, still requires positioning the patient in a conventional large MRI magnet. This environment can result in deficient images because the various orientations of the RF coil, e.g., in an artery, will not be positioned always colinearly with the RF excitation field.
This problem has been resolved by U.S. Pat. No. 5,572,132, to Pulyer, et al., entitled, “MRI probe for external imaging,” whose disclosure is incorporated herein by reference, wherein an MRI catheter for endoscopical imaging of tissue of the artery wall, rectum, urinal tract, intestine, esophagus, nasal passages, vagina and other biomedical applications is described.
The invention teaches an MRI spectroscopic probe having an external background magnetic field B0 (as opposed to the internal background magnetic filed of the large horizontal bore superconducting magnet.) The probe comprises (i) a miniature primary magnet having a longitudinal axis and an external surface extending in the axial direction and (ii) a RF coil surrounding and proximal to said surface. The primary magnet is structured and configured to provide a symmetrical, preferably cylindrically shaped, homogeneous field region external to the surface of the magnet. The RF coil receives NMR signals from excited nuclei. For imaging, one or more gradient coils are provided to spatially encode the nuclear spins of nuclei excited by an RF coil, which may be the same coil used for receiving NMR signals or another RF coil.
U.S. Pat. No. 6,315,981 to Unger, entitled, “Gas filled microspheres as magnetic resonance imaging contrast agents,” whose disclosure is incorporated herein by reference, describes the use of gas filled microspheres as contrast agents for magnetic resonance imaging (MRI). Unger further describes how gas can be used in combination with polymer compositions and possibly also with paramagnetic, superparamagnetic, and liquid fluorocarbon compounds as MRI contrast agents. It is further shown how the gas stabilized by polymers would function as an effective susceptibility contrast agent to decrease signal intensity on T2 weighted images; and that such systems are particularly effective for use as gastrointestinal MRI contrast media.
Ingestible radio pills, which are ingestible capsules containing a transmitter are known. In 1964 research at Heidelberg University developed a pill for monitoring pH of the gastrointestinal tract. (Noller, H. G., “The Heidelberg Capsule Used For the Diagnosis of Pepic Diseases”, Aerospace Medicine, February 1964, pp. 15-117.)
U.S. Pat. No. 4,844,076, to Lesho, et al., of July 1989, entitled, “Ingestible size continuously transmitting temperature monitoring pill,” whose disclosure is incorporated herein by reference, describes a temperature responsive transmitter, encapsulation in an ingestible size capsule. The capsule is configured to monitor average body temperature, internally. The ingestible size temperature pill can be configured in a rechargeable embodiment. In this embodiment the pill uses the inductive coil in the tank circuit as the magnetic pickup to charge a rechargeable nickel cadmium battery.
U.S. Pat. No. 5,279,607, to Schentag, et al., “Telemetry capsule and process,” whose disclosure is incorporated herein by reference, describes an ingestible capsule and a process for delivery, particularly repeatable delivery, of a medicament to the alimentary canal. The ingestible capsule is essentially non-digestible capsule, which contains an electric energy emitting means, a radio signal transmitting means, a medicament storage means and a remote actuatable medicament releasing means. The capsule signals a remote receiver as it progresses through the alimentary tract in a previously mapped route and upon reaching a specified site is remotely triggered to release a dosage of medicament.
Similarly, U.S. Pat. No. 5,395,366, to D'Andrea et al., entitled, “Sampling capsule and process,” whose disclosure is incorporated herein by reference, describes a similar ingestible capsule and a process for sampling of fluids in the to the alimentary canal.
U.S. Pat. No. 5,604,531, to Iddan, et al., entitled, “In vivo video camera system,” whose disclosure is incorporated herein by reference, describes a video camera system, encapsulated within an ingestible pill, arranged to pass through the entire digestive tract, operating as an autonomous video endoscope. The ingestible pill includes a camera system and an optical system for imaging an area of interest onto the camera system, and a transmitter, which relays the video output of the camera system to an extracorporeal reception system. A light source is located within a borehole of the optical system.
Similarly, U.S. Patent Application 20010035902, to Iddan, G. J., et al., entitled, “Device and system for in vivo imaging,” Whose disclosure is incorporated herein by reference, describes a system and method for obtaining in vivo images. The system contains an imaging system and an ultra low power radio frequency transmitter for transmitting signals from the CMOS imaging camera to a receiving system located outside a patient. The imaging system includes at least one CMOS imaging camera, at least one illumination source for illuminating an in vivo site and an optical system for imaging the in vivo site onto the CMOS imaging camera.
U.S. Pat. No. 6,324,418, to Crowley, et al., entitled, “Portable tissue spectroscopy apparatus and method,” whose disclosure is incorporated herein by reference, describes a portable tissue spectroscopy apparatus including at least one light source, at least one light detector, a power source and a controller module, all disposed inside a housing that is insertable inside a body. The housing may be in the form of a hand-holdable probe or in the form of a capsule that can be swallowed or implanted in the body. The probe further includes a display mounted at a proximal end of the housing for displaying tissue characteristics. The capsule further includes a transmitter mounted inside the capsule and a receiver placed outside the body for transmitting signals representative of tissue characteristics to a remote receiver.
The capsule includes one or more light emitters and one or more light detectors. The light detectors may be located in various places within the housing for detecting spectroscopic properties from various tissues near the capsule. The capsule may further include other types of emitters and sensors. The additional emitters and sensors, for example, can relate to electromagnetic radiation, pressure, temperature, x-ray radiation and/or heat. In one embodiment, the capsule further comprises an acoustic transmitter and a receiver for measuring flow of fluid or for detecting echo location of the capsule. In another embodiment, the capsule further includes diagnostic sensors such as monitoring electrodes, pressure sensors and temperature sensors.
U.S. Pat. No. 5,415,1818, to Hogrefe, et al., entitled, “AM/FM multi-channel implantable/ingestible biomedical monitoring telemetry system,” whose disclosure is incorporated herein by reference, describes a wireless multi-channel circuit for telemetering signals representing physiological values from a point in a human body to a receiver outside of the body. The two signals, S1 and S2, other than the temperature signal are used to provide two frequency modulated signals summed by an amplifier with the summed FM signal then being applied to amplitude modulate a carrier whose frequency varies as a function of temperature. The resulting FM/AM signal is telemetered inductively outside of the body to an external receiver. Appropriate demodulation, filter, and shaping circuits within the external circuit detect the FM signals and thus produce three independent frequencies two of which are the original physiological variables and the third a function of local temperature. Real time plot of the two physiological variables can be obtained using FM discriminators while the temperature dependent frequency is best monitored by a counter.
Similarly, U.S. Pat. No. 5,842,977 to Lesho, et al., entitled, “Multi-channel pill with integrated optical interface,” whose disclosure is incorporated herein by reference, describes an optical interface incorporated into a multi-channel telemetry device, used to provide data representing physiological conditions.
Methods of tracking ingestible devices, such as radio pills, are known. U.S. Pat. No. 5,279,607, to Schentag, et al., entitled, “Telemetry capsule and process,” and U.S. Pat. No. 5,395,366, to D'Andrea et al., entitled, “Sampling capsule and process,” described hereinabove, include extracorporeal apparatus having a plurality of antennae, used to determine the geographic position of the capsule within the gastrointestinal tract. For example, at least three antennae, located at different distances from the point source, and dedicated algorithms may be used to determine the precise location of the capsule, at any time.
U.S. Pat. No. 6,082,366 to Andrii et al., entitled, “Method and arrangement for determining the position of a marker in an organic cavity,” whose disclosure is incorporated herein by reference, describe a method for pinpointing a marker such as an ingestible capsule. The method requires that the patient be positioned within a magnetic field, for example, as used for MRI imaging.
Notwithstanding the high level of sophistication of the aforementioned systems, gastrointestinal pathologies, and particularly, occult tumors have remained elusive in medical diagnosis. There is thus a widely recognized need for, and it would be highly advantageous to have, a device and method for detecting pathologies in the gastrointestinal tract devoid of the above limitations.